PROJECT SUMMARY OVERALL We propose a Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Collaborative Research Center at The Jackson Laboratory (JAX ME/CFS CRC) to identify the fundamental mechanisms by which a tri- component network of systems?the microbiome, metabolism and the immune system?interact to cause or exacerbate disease. ME/CFS is a debilitating illness that lacks widely accepted therapies for its management as well as meaningful understanding of its biological underpinnings. Mounting evidence indicates a significant role for immunological abnormalities, which are thought to contribute to disease progression. The microbiome recently emerged as a potential contributor to immune perturbations, as it is intimately linked with immune activation and homeostasis as well as host metabolic changes, and its dysbiosis has been linked to chronic inflammation. Metabolomic studies suggest altered metabolic states in ME/CFS patients compared to healthy controls, which could have downstream?or reciprocal?effects on sugar, energy levels, immune cell activity, and microbial dysbiosis. However, small sample sizes, lack of cohesive clinical data and biological sample collection, and overall focus on one component of the network has limited the impact of these studies. The JAX ME/CFS CRC seeks to transform the landscape of knowledge of ME/CFS using a multi-disciplinary systems biology approach to integrate phenotypic and functional immune changes in ME/CFS patients with microbiome and metabolic parameters. We hypothesize that the immune system's etiological role in ME/CFS is predicated on two major factors: 1) that immune cells are programmed to respond aberrantly to environmental stimuli, and 2) that ME/CFS patients harbor microbes that aberrantly stimulate immune cells, either directly or through metabolic byproducts. To probe this hypothesis, we structured the JAX ME/CFS CRC around two integrated research projects and a prospective cohort of ME/CFS patients and healthy controls in which blood, fecal samples and a range of clinical parameters are acquired longitudinally. Our Center will bring together ME/CFS clinicians, experts in immunology, microbiome, and computational biology, and community stakeholders to achieve our scientific goals and maximize the impact of our research on those affected by the disease. Our Aims are: 1) Develop a comprehensive and prospective database of immune, metabolomics and microbiome profiles of ME/CFS patients (Clinical Research Project); 2) Establish a platform for mechanistic discoveries on role of ME/CFS microbiota and immune response (Basic Research Project); 3) Rapidly implement recruitment of the ME/CFS prospective clinical cohort (Clinical Core); and 4) Coordinate an integrative, multidisciplinary group in ME/CFS research (Admin Core). In addition, we will capitalize on both on scientific expertise and vast mouse genetic resource of the JAX to develop highly collaborative inter-CRC projects to understand role of epigenetics, developing mouse models for microbiome-immune interactions and neurological symptoms. Together, these will allow strategies for patient diagnosis and future clinical trials.